Regulation of synaptic scaling by action potential–independent miniature neurotransmission

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Action potential (AP)‐independent spontaneous release was once thought to represent a functionally unimportant release of synaptic vesicles, whose actual role was limited to spike‐dependent release. In the last few years it has become clear that spontaneous release and AP‐dependent release are two different forms of transmission (Kavalali, 2015). Recent work has demonstrated that spontaneous release is important for several aspects of nervous system development, including setting synaptic strength through a form of plasticity known as homeostatic synaptic scaling. Almost 20 years ago, a fundamentally important series of observations were published. They demonstrated that when spike activity was blocked for days in cultured cortical networks, neurons responded in what appeared to be a compensatory direction by increasing the strength of all their excitatory synaptic inputs, as measured by miniature excitatory postsynaptic current (mEPSC) amplitude (Turrigiano, 2012; Turrigiano, Leslie, Desai, Rutherford, & Nelson, 1998). This increase occurred across the entire distribution of mEPSC amplitudes in a multiplicative or “scaled” manner (e.g., all amplitudes became twice as large); in this way relative differences in synaptic strength achieved through Hebbian means were maintained. This initial study showed that 2‐day block of either APs with TTX or AMPA receptor activation (AMPAergic transmission) with CNQX triggered upward scaling, which was mediated by an increase in the postsynaptic sensitivity to glutamate. These initial results have proven extremely robust, as they have been identified in hippocampal primary cultures and slices, spinal cultures, as well as many other tissues in vitro and in vivo (Deeg & Aizenman, 2011; Goel et al., 2006; Gonzalez‐Islas & Wenner, 2006; O'Brien et al., 1998; Thiagarajan, Piedras‐Renteria, & Tsien, 2002). Scaling has been proposed to act to contribute to the homeostatic maintenance of spiking levels, which is thought to be triggered by reduced spiking to restore the spike rate to a set point. However, the picture has become more complicated as recent observations demonstrate that scaling can be triggered by altering AP‐independent spontaneous release. We will now discuss these reports as they relate to divergent experimental systems.
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